A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep

Alex Clop^1, 6, Fabienne Marcq^1, 6, Haruko Takeda^1, 6, Dimitri Pirottin^1, 6, Xavier Tordoir¹, Bernard Bibé², Jacques Bouix², Florian Caiment¹, Jean-Michel Elsen², Francis Eychenne², Catherine Larzul², Elisabeth Laville³, Françoise Meish¹, Dragan Milenkovic⁴, James Tobin⁵, Carole Charlier¹ & Michel Georges¹

¹  Unit of Animal Genomics, Department of Animal Production, Faculty of Veterinary Medicine & Centre for Biomedical Integrative Genoproteomics, University of Liège (B43), 20 Boulevard de Colonster, 4000 Liège, Belgium.

²  Institut National de la Recherche Agronomique–Station d'Amélioration Génétique des Animaux (INRA-SAGA), BP 52627, 31326 Castanet-Tolosan CEDEX, France.

³  Station de Recherches sur la Viande, INRA, Theix, 63122 Saint-genès-Champanelle, France.

⁴  INRA/Université de Limoges, Faculté des Sciences, 87060 Limoges Cedex, France.

⁵  Cardiovascular and Metabolic Diseases, Wyeth Research, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.

⁶  These authors contributed equally to this work.

Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.

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